Abstract
Background Hypersensitivity pneumonitis (HP) is classified into nonfibrotic and fibrotic phenotypes. Patients with nonfibrotic HP often experience recurrence and develop fibrosis, whereas those with fibrotic HP have a poor prognosis. Although antigen avoidance has long been the first line of treatment for HP, its impact on prognosis has been poorly reported.
Methods Medical records of 121 patients with HP diagnosed by new diagnostic criteria of American Thoracic Society/Japanese Respiratory Society/Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) guidelines and treated at our institution in Saitama, Japan, were retrospectively analysed. HP was classified into nonfibrotic and fibrotic phenotypes and six HP subtypes: summer-type, bird-related, home-related and occupational HP, humidifier lung, and hot tub lung. Achievement of reduced exposure to inciting agents was divided into complete antigen avoidance (CAA) and incomplete antigen avoidance (IAA) by HP subtype.
Results Of the 74 patients with nonfibrotic HP, 30 achieved CAA and experienced no recurrence or development of fibrosis. In the remaining 44 patients with IAA, 24 (54.5%) experienced recurrence and/or development of fibrosis. The all-cause 5-year mortality rate in the 47 patients with fibrotic HP was 47.8%. Negative prognostic factors of HP-related mortality in these patients were <50% lymphocytes in bronchoalveolar lavage (BAL) and honeycombing. Multivariate analysis showed a tendency for IAA to be related to poorer survival (hazard ratio 3.452, 95% CI 0.964–12.359, p=0.057).
Conclusions In the patients with nonfibrotic HP, CAA resulted in no recurrence or development of fibrosis and longer survival. In the patients with fibrotic HP, <50% lymphocytes in BAL and honeycombing were negative prognostic factors for mortality.
Abstract
Complete antigen avoidance reduces the recurrence and development of fibrosis in patients with nonfibrotic HP and may be related to longer survival in patients with fibrotic HP https://bit.ly/3E5EVLR
Introduction
Hypersensitivity pneumonitis (HP) is an inflammatory and/or fibrotic disease affecting the lung parenchyma and small airways. It typically results from an immune-mediated reaction provoked by an overt or occult inhaled antigen in susceptible individuals [1]. Although various alternative definitions of HP have been proposed [2–5], clinical practice guidelines were developed by the American Thoracic Society (ATS), the Japanese Respiratory Society (JRS) and the Asociación Latinoamericana del Tórax (ALAT) [6] for the accurate diagnosis of HP. Accurate and timely diagnosis can help patients avoid culpable environmental factors known to induce HP and potentially change the disease course [7–9].
HP was historically categorised as acute, subacute or chronic [5]. However, these categories are not easily demarcated, and their delineation has been variable and arbitrary in many studies [10–12]. Because the presence of radiographic or histopathological fibrosis is the primary determinant of prognosis [7–9, 13–19], the ATS/JRS/ALAT guideline categorises HP as either nonfibrotic or fibrotic. Patients with nonfibrotic HP often experience recurrence and develop fibrosis, whereas those with fibrotic HP have a poor prognosis. Whether complete antigen avoidance (CAA) improves the outcome of patients with nonfibrotic or fibrotic HP requires further study. We hypothesised that CAA would reduce the incidences of recurrence and fibrosis development in nonfibrotic HP patients and would prolong survival in patients with fibrotic HP.
Thus, the present study aimed to retrospectively review the medical records of 121 patients with HP diagnosed according to the new diagnostic criteria of the ATS/JRS/ALAT guideline to assess both the relationship of CAA with recurrence or fibrosis development in patients with nonfibrotic HP and prognostic factors including CAA in patients with fibrotic HP.
Study design and methods
Study design
We performed a retrospective cohort study in Saitama Cardiovascular and Respiratory Center, Saitama, Japan. We studied 121 HP patients aged >18 years who fulfilled the 2020 ATS/JRS/ALAT diagnostic criteria of definite, high confidence and moderate confidence, and were newly diagnosed from 1991 through 2016 (table 1). Following publication of the ATS/JRS/ALAT clinical practice guideline in 2020, we reviewed all clinical, radiographic, bronchoalveolar lavage (BAL) and pathological data, treatments, CAA and outcomes from medical records of all patients who had been diagnosed as having HP. Patients with a diagnosis of HP of low confidence or not excluded were not included. Standard high-resolution computed tomography (HRCT) protocols were used to obtain images for evaluation. The scans were reviewed independently in a blinded fashion by two observers (N.T. and T.K.). Scans consistent with fibrotic HP contained irregular fine or coarse reticulation with architectural lung distortion and traction bronchiectasis and were divided into two groups: those with and without honeycombing. In cases of disagreement, consensus was obtained following further review. All patients were classified as having fibrotic or nonfibrotic HP based on the presence or absence, respectively, of radiological fibrosis. HRCT scan features and histopathological criteria for the diagnosis of HP were classified according to the following three patterns: typical HP, compatible HP or indeterminate HP and HP, probable HP or indeterminate for HP, respectively (table 1). Based on exposure history and/or serum antibody testing, HP was classified into six categories: summer-type HP, bird-related HP, home-related HP, occupational HP (including mushroom worker's lung, isocyanate alveolitis, farmer's lung and workplace-associated HP due to Aspergillus fumigatus), humidifier lung and hot tub lung (table 2).
All patients are advised to reduce or avoid offending environmental factors, and reduction in the intensity of exposure to inciting antigens was classified into the categories of CAA and incomplete antigen avoidance (IAA). In patients with summer-type, bird-related and home-related HP, changing homes was considered to be CAA, whereas renovation, clean-up or stopping breeding of birds but continuing to live in the same house was considered IAA. In patients with occupational HP, humidifier lung and hot tub lung, job change or job relocation, not using the humidifier and not using the hot tub, respectively, were considered CAA (table 2). Patients were followed through December 2018 or until death before then. Survival status was obtained from medical records and/or telephone interviews. In patients with nonfibrotic HP, we examined whether IAA was associated with recurrence (re-exacerbation of respiratory symptoms and ground-glass opacities on HRCT) and/or fibrosis development and searched for predictors of recurrence and/or fibrosis development in the patients with nonfibrotic HP who did not do CAA. In the patients with fibrotic HP, prognosis and prognostic markers were investigated.
Data analysis
Categorical baseline characteristics are summarised by frequency and percent, and continuous characteristics are reported as the median (interquartile range, IQR). We compared baseline characteristics and therapy for nonfibrotic and fibrotic HP by Fisher's exact test or Wilcoxon test in accordance with nominal and continuous variables, respectively. Recurrence and/or fibrosis development in each patient group with or without CAA was estimated by Kaplan–Meier analysis. Because recurrence and/or fibrosis development occurred only in the IAA group, we investigated potential risk factors of recurrence and/or developing fibrosis only in these patients. We chose the following variables for entry into univariate Cox regression analysis: sex, age, smoking history, HP subtype, presence of fever, BAL lymphocytes, BAL neutrophils, BAL CD4/CD8, forced vital capacity (FVC) % predicted, diffusing capacity for carbon monoxide (DLCO) % predicted, partial pressure of arterial oxygen (PaO2), partial pressure of arterial carbon dioxide (PaCO2), alveolar–arterial oxygen difference (A-aDO2), erythrocyte sedimentation rate, C-reactive protein (CRP), sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6), pulmonary surfactant protein D (SP-D) and steroid therapy. Survival times of patients with nonfibrotic and fibrotic HP were estimated by Kaplan–Meier analysis. All-cause mortality rates were compared with a log-rank test. To investigate potential risk factors of mortality of patients with fibrotic HP, we used the following variables for entry into univariate Cox regression analysis: sex, age, smoking history, type of disease onset, HP subtype, BAL lymphocytes, BAL neutrophils, BAL CD4/CD8, FVC % predicted, DLCO % predicted, PaO2, PaCO2, A-aDO2, erythrocyte sedimentation rate, CRP, KL-6, SP-D, HRCT findings of honeycombing, traction bronchiectasis, and lung distortion, steroid therapy and CAA. We then performed univariate and multivariate Cox regression analysis with backward variable selection. Fibrotic HP can be divided clinically into two types of onset: insidious type, which develops without a history of acute episodes but is a slowly progressive chronic respiratory disease, and recurrent type, which develops after recurrent acute episodes. A p-value of <0.05 was considered to be statistically significant in all analyses. Missing data were categorised as “unknown” and were entered into each statistical analysis model. All data were analysed with SAS version 9.1.3 (SAS Institute, Cary, NC, USA). The Saitama Cardiovascular and Respiratory Center institutional review board approved this study (no. 2020034).
Results
Patient characteristics
Of the 121 patients, 60 (49.6%) were female. Median patient age was 63.0 years. Phenotypes included nonfibrotic (61.2%) and fibrotic (38.8%) HP. HP subtypes included summer-type (43.0%), bird-related (26.4%), home-related (14.0%), occupational (9.1%), humidifier lung (6.6%) and hot tub lung (0.8%) (table 3).
Compared with patients with fibrotic HP, those with nonfibrotic HP were significantly more likely to be female, nonsmokers, have a shorter duration of symptoms, and have fever and summer-type HP. HRCT scan features of ill-defined centrilobular nodules, ground-glass opacities, and mosaic attenuation, BAL lymphocytosis, low CD4/CD8 of BAL lymphocytes, higher CRP, lower SP-D, lower PaO2, lower PaCO2, higher A-aDO2 and higher FVC % predicted all occurred significantly more frequently in those with nonfibrotic HP. Steroid therapy was more frequently administered to patients with fibrotic versus nonfibrotic HP, but CAA was more frequently done by patients with nonfibrotic versus fibrotic HP.
HP recurrence/fibrosis in nonfibrotic HP
Of the 74 patients with nonfibrotic HP, 30 did CAA and experienced no recurrence or fibrosis development, and complete resolution was maintained at the last follow-up regardless of whether short-course steroid therapy was administered (figure 1a). In the remaining 44 patients not doing CAA, recurrence and/or fibrosis development occurred in 24 (54.5%) patients, and the median time to recurrence and/or developing fibrosis was 3.7 years. Of the 20 patients who did not experience a recurrence or develop fibrosis, all maintained complete resolution. The log-rank test showed a significant difference between event-free curves in the patients with CAA and IAA (p<0.001) (figure 2). Among the 24 patients with recurrence and/or fibrosis development, recurrence occurred in 22 patients and fibrosis developed in seven (figure 1b). The first episode of recurrence or fibrosis development was recurrence only in 21 patients, fibrosis only in two patients, and both in one patient. Of the 21 patients with recurrence, three did CAA, and none experienced recurrence or developed fibrosis. Of the remaining 18 patients without CAA, 11 patients experienced a second recurrence, and three experienced recurrence and developed fibrosis. Of the 11 patients with a second recurrence, two patients did CAA, and neither experienced recurrence nor developed fibrosis. Of the remaining nine patients without CAA, two patients experienced a third recurrence, and one patient experienced recurrence and developed fibrosis. Among the 74 patients in the nonfibrotic HP group, none of the seven patients with fibrosis development died, but six patients had progressive lung fibrosis, for which two required home oxygen therapy.
In a univariate Cox proportional hazard model, no factor was found to be a risk factor for recurrence and/or fibrosis development among the patients with nonfibrotic HP who did not do CAA (table 4).
Mortality and causes of death
Death from any cause occurred in 28 (23.1%) patients over a median follow-up period of 5.6 years (IQR, 2.7–9.2 years), and the overall cumulative 5- and 10-year mortality rates were 19.3% and 31.0%, respectively. The respective overall cumulative 5- and 10-year mortality rates were 0.0% and 2.9% in the nonfibrotic HP group and 47.8% and 79.6% in the fibrotic HP group. The log-rank test showed a significant difference between survival curves in patients with nonfibrotic versus fibrotic HP (p<0.001, figure 3). Three patients with nonfibrotic HP died from non-pulmonary malignancy (two patients), and unknown cause (one patient), and 25 patients with fibrotic HP died from respiratory failure due to HP progression (13 patients), acute exacerbation of HP (11 patients) and pulmonary tuberculosis (one patient).
Prognostic factors of HP-specific mortality
In a multivariate Cox proportional hazard model, <50% lymphocytes in BAL and HRCT features of honeycombing were found to be negative prognostic factors of HP-specific mortality in the patients with fibrotic HP (table 5). IAA showed a tendency to be related to poorer survival according to the multivariate analysis (hazard ratio 3.452, 95% CI 0.964–12.359, p=0.057).
Discussion
The patients in the present study with nonfibrotic HP who did CAA did not experience recurrence or develop fibrosis and sustained their clinical improvement, whereas those with fibrotic HP not doing CAA showed a trend towards poor prognosis. Although antigen avoidance has long been the first line of treatment for HP, its impact on prognosis has been poorly reported.
De Sadeleer et al. [9] reported that antigen avoidance improved the lung function trajectory (FVC % predicted, DLCO % predicted) in patients with nonfibrotic HP but did not improve mortality in patients with nonfibrotic or fibrotic HP. Gimenez et al. [18] investigated the relationship of antigen avoidance and survival in patients with fibrotic HP. Among their 112 patients, 61 (54.4%) patients reported antigen avoidance and 25 (41%) reported sustained clinical improvement. Clinical improvement with antigen avoidance (not just antigen avoidance itself) was associated with reduced mortality. Some patients with insidiously progressive fibrotic HP do not show significant improvement of symptoms even with antigen avoidance [20], and in the Gimenez et al. study, survival was compared in patients who achieved sustained clinical improvement after avoiding exposure and in patients who did not achieve clinical improvement and those not avoiding exposure. Fernández Pérez et al. [7] found that identifying an antigen was associated with improved survival in patients with chronic HP. In this report, antigens could be identified only in 67 (47%) of 142 patients with HP, and at least 27 patients (40%) had occupational HP or hot tub lung, for which the antigen could easily be completely avoided, and had a good prognosis [21, 22]. In the present study, the inciting antigen was identified in nearly all patients other than five of the 17 patients with home-related HP.
Unfortunately, appropriate means of antigen avoidance are not well defined [23]. Craig et al. [24] and Sema et al. [25] reported that high levels of bird antigen can be detected for a prolonged period after bird removal and environmental clean-up in patients with bird-related HP. In fact, two of our four patients with bird-related nonfibrotic HP who continued to live in the same house after bird removal experienced a recurrence. Tsutsui et al. [26] reported that the amount of avian antigen in household dust is related to disease progression and prognosis in chronic bird-related HP, indicating that fibrosis development and prognosis in patients with HP depend on the degree of antigen avoidance. Therefore, to clearly classify whether CAA was done, we defined CAA in each type of HP (table 2). Especially for summer-type, bird-related and home-related HP, we defined changing home to be the only complete change of environment satisfying CAA. CAA is straightforward for patients with occupational HP (job change or relocation), humidifier lung (no use) and hot tub lung (no use). When limited to the patients with these types of HP, only 15 of the 58 patients with nonfibrotic HP and six of the 45 patients with fibrotic HP actually changed homes.
Although the efficacy of antigen avoidance in patients with nonfibrotic HP is well established [9, 22, 27, 28], some reports suggest that their symptoms do not progress and their pulmonary function does not always decline even without adequate antigen avoidance [29–31]. Of our 44 patients with nonfibrotic HP without CAA, 24 experienced recurrence and/or developed fibrosis, whereas the remaining 20 patients had no recurrence afterward and achieved sustained clinical improvement (figure 1a). Five patients did CAA after one or two recurrences, and none of them had recurrence or fibrosis after CAA (figure 1b). These results suggest that if a patient who could not do CAA at the time of diagnosis still has a recurrence after efforts to reduce the antigen level, CAA might be recommended again at the new recurrence. Sema et al. [25] found that the amounts of avian antigens in household dust were related to disease progression and poor prognosis in chronic bird-related HP, and even if changing homes is not possible for various reasons, efforts should be made to thoroughly reduce the amounts of antigen by clean-up and renovation.
Patients with nonfibrotic HP have a low mortality rate [9, 11, 18], and none of the present study patients died of HP-related causes. Among the 74 patients with nonfibrotic HP, some experienced repeated recurrences without developing fibrosis, but seven patients also developed fibrosis. Recently, genomics has begun to have an important role in researching the mechanisms underlying the susceptibility to and progression of pulmonary fibrosis [32]. Ley et al. [33] found that among patients with chronic HP, the mucin 5B (MUC5B) minor allele and shorter telomere length measured in peripheral blood leukocytes were associated with the extent of radiographic fibrosis. Future studies are needed to determine whether the background genetics of patients with nonfibrotic HP may influence the onset of pulmonary fibrosis.
Fibrosis in HP is a poor prognostic factor, with median survival time ranging between 4.9 and 9.2 years [7–9, 11, 17–19]. The prognosis of honeycomb HP is even poorer, with Salisbury et al. [11] reporting a survival time of 2.8 years, similar to that for idiopathic pulmonary fibrosis with honeycombing. Twenty-six of the 47 patients with fibrotic HP had honeycomb HP, and their median survival was 3.69 years, similar to that of Salisbury et al. Of the eight patients with fibrotic HP with CAA, all three patients who died during the follow-up period had honeycombing. The median survival times of patients with honeycomb HP with CAA (n=4) and with IAA (n=22) were 4.54 years and 3.15 years, respectively, but the difference was not significant (p=0.508) because of the small number of patients. Additional study is needed to clarify whether CAA should be recommended for honeycomb HP.
An important strength of this study was that HP was diagnosed by the new diagnostic criteria of the ATS/JRS/ALAT guideline, all patients could be classified into six HP subtypes, and the decrease in exposure to inciting agents was divided into the grades of CAA or IAA by HP subtype. So, although this was a retrospective study performed in a single hospital, these results could have some generalisability.
Our study has some limitations. First, the distinction between CAA and IAA was strictly defined in this study. Although the definition of CAA in occupational HP, humidifier lung and hot tub lung was not so difficult, the distinction between CAA and IAA is not so easily defined for summer-type, bird-related and home-related HP. Actually, in summer-type and home-related HP, after the colonising places in the patients’ houses were intensively cleaned and the patients returned home, some experienced recurrence whereas others did not. Thus, in patients without recurrence, this type of intensive cleaning would be considered CAA. Similarly, in bird-related HP, some patients experienced recurrence after stopping the breeding of birds but others did not. However, at least no one experienced a recurrence or developed fibrosis after CAA according to our definition. The accuracy of our distinction between CAA and IAA should be re-evaluated. Second, because only eight of the 47 patients with fibrotic HP did CAA, the conclusion from the multivariate analysis that IAA tended to be related to poorer survival could indicate bias due to the small sample size. Third, although 20–53% of patients included in previous reports had unknown inciting antigen [7–9], all patients in the present study had an inciting antigen or an identified site of exacerbation by inhalation provocation tests and specific antibodies. We carefully judged the indication for surgical lung biopsy in fibrotic diffuse lung diseases and performed it in only 10 of the 121 patients. Because most patients with unknown inciting antigen and no histopathological findings are considered “low confidence” or “not excluded” in the ATS/JRS/ALAT guidelines, this study did not include patients with unknown inciting antigen without histopathological findings of HP pattern and thus may not reflect the whole population of HP.
Conclusions
In this analysis, CAA done by patients with nonfibrotic HP was related to no recurrence and/or no fibrosis development. Moreover, CAA was useful after a second or third recurrence. However, nearly all of these patients with fibrosis development developed progressive lung fibrosis. In the patients with fibrotic HP, <50% lymphocytes in BAL and radiographic honeycombing were negative prognostic factors for HP-related mortality, and CAA was suggested to be related to longer survival. These findings may have important implications for the care of patients with HP in terms of the need for CAA.
Acknowledgements
We sincerely thank Tsutomu Yanagisawa, Kazuyoshi Kurashima, Naho Kagiyama and Yotarou Takaku of the Dept of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, for diagnosing and treating the HP in the study patients.
Footnotes
Provenance: Submitted article, peer reviewed.
Author contributions: T. Nishida takes responsibility for and is the guarantor of the content of the manuscript, including the data and analysis. E. Kawate, T. Ishiguro, T. Kanauchi, Y. Shimizu and N. Takayanagi made substantial contributions to the conception or design of the work; and the acquisition, analysis and interpretation of data for the work; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflict of interest: T. Nishida has nothing to disclose.
Conflict of interest: E. Kawate has nothing to disclose.
Conflict of interest: T. Ishiguro has nothing to disclose.
Conflict of interest: T. Kanauchi has nothing to disclose.
Conflict of interest: Y. Shimizu has nothing to disclose.
Conflict of interest: N. Takayanagi has nothing to disclose.
Support statement: All work was performed at the Saitama Cardiovascular and Respiratory Center. This study was partially supported by a grant from Saitama Cardiovascular and Respiratory Center (Grant No. 12-20ZD). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received July 22, 2021.
- Accepted October 13, 2021.
- Copyright ©The authors 2022
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